Branched photoswitchable tethered ligands enable ultra-efficient optical 
control and detection of G protein-coupled receptors in vivo

Acosta-Ruiz, Amanda; Gutzeit, Vanessa A.; Skelly, Mary Jane; Meadows, Samantha; Lee, Joon; Parekh, Puja; Orr, Anna G.; Liston, Conor; Pleil, Kristen E.; Broichhagen, Johannes; Levitz, Joshua

doi:10.1016/j.neuron.2019.10.036

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Branched photoswitchable tethered ligands enable ultra-efficient optical control and detection of G protein-coupled receptors in vivo

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Broichhagen, Johannes
Chemical Biology, Max Planck Institute for Medical Research, Max Planck Society;

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https://doi.org/10.1016/j.neuron.2019.10.036
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Citation

Acosta-Ruiz, A., Gutzeit, V. A., Skelly, M. J., Meadows, S., Lee, J., Parekh, P., et al. (2020). Branched photoswitchable tethered ligands enable ultra-efficient optical control and detection of G protein-coupled receptors in vivo. Neuron, 105, 1-18. doi:10.1016/j.neuron.2019.10.036.

Cite as: https://hdl.handle.net/21.11116/0000-0005-45A4-4

Abstract

The limitations of classical drugs have spurred the development of covalently tethered photoswitchable ligands to control neuromodulatory receptors. However, a major shortcoming of tethered photopharmacology is the inability to obtain optical control with an efficacy comparable with that of the native ligand. To overcome this, we developed a family of branched photoswitchable compounds to target metabotropic glutamate receptors (mGluRs). These compounds permit photo-agonism of G i/o-coupled group II mGluRs with near-complete efficiency relative to glutamate when attached to receptors via a range of orthogonal, multiplexable modalities. Through a chimeric approach, branched ligands also allow efficient optical control of G q-coupled mGluR5, which we use to probe the spatiotemporal properties of receptor-induced calcium oscillations. In addition, we report branched, photoswitch-fluorophore compounds for simultaneous receptor imaging and manipulation. Finally, we demonstrate this approach in vivo in mice, where photoactivation of SNAP-mGluR2 in the medial prefrontal cortex reversibly modulates working memory in normal and disease-associated states.